Thionyl Chloride → Enzalutamide Impurity 20

HRID 38759Notes

Reaction equation

HRID 38759 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([F:26])[CH:18]=3)[C:10]2=S)=[CH:5][C:4]=1[C:28]([F:31])([F:30])[F:29])#[N:2].S(Cl)(Cl)=[O:33]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([F:26])[CH:18]=3)[C:10]2=[O:33])=[CH:5][C:4]=1[C:28]([F:31])([F:30])[F:29])#[N:2]

Participants

3

Reactant 2

HCID 24386Thionyl ChlorideHCID 46898522Enzalutamide carboxylic acid

Product 1

HCID 46898525Enzalutamide Impurity 20

Procedure

A solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoic acid (50 mg, 0.11 mmol) in thionyl chloride (0.5 mL, 67.7 mmol) was stirred at 90 deg C. for 15 h. The reaction mixture was concentrated under reduced pressure to dryness. Ice-water (20 mL) was added into the residue and the product was extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford crude product, which was purified by reverse phase HPLC to yield 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoic acid. 1H NMR DMSO-d6 (FREE BASE): δ (ppm) 8.39 (d, 1H), 8.25 (s, 1H), 8.1 (d, 1H), 8.0 (t, 1H), 7.45 (d, 1H), 7.4 (d, 1H), 1.58 (s, 6H).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure to dryness
  2. additionIce-water (20 mL) was added into the residue
  3. extractionthe product was extracted with ethyl acetate (60 mL)
  4. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  5. customevaporated under reduced pressure
  6. customto afford crude product, which
  7. customwas purified by reverse phase HPLC

Sources & evidence

ORD record
ord-aa159dab5e51485486537781e3e944d1
Source dataset
uspto-grants-2013_09
Patent number
US08524755B2

Reaction notes

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